Defining strategies to increase the mass of functional b-cells is an alternative approach that could result in major advances for the cure of diabetes. Several lines of evidence suggest that Akt/PKB is an important molecule for the regulation of b-cell mass in adult pancreas. Yet the role of Akt signaling in the regulation of pancreas development and acquisition of endocrine fate has not been assessed. The overall goal of this proposal is to extend previous observations in the adult pancreas by studying the role of Akt signaling in the differentiation program of the pancreas. In these studies the hypothesis that Akt regulates b-cell mass by controlling the relative balance between self-renewal and differentiation of pancreatic and endocrine progenitors will be tested. These experiments will be performed by studying mice with targeted activation of Akt signaling and cell lineage tracing in pancreatic progenitors expressing pdxl and neurogenin3. These mice will be generated by crossing conditional transgenic mice containing a constitutively active form of Akt that can be induced in a Cre-excision conditional manner with transgenic animals expressing Cre recombinase under the control of the pdxl and neurogenin3 promoter. Cells expressing Akt will also be tagged with EGFP allowing us to performed cell lineage tracing experiments. These experiments are designed to begin to elucidate the genetic pathways involved in the regulation of pancreas development and will attempt to increase the pool of pancreatic and endocrine progenitors by activating Akt dependent self-renewal and proliferation of progenitor cells. Expansion of a tagged progenitor pool will allow the isolation of these cells for characterization in in vitro studies. Expansion of progenitor cell in vitro could be an invaluable tool to generate beta-cells by in vitro differentiation. From a therapeutic standpoint, pharmacologic manipulation of the PI3K/Akt signaling in vivo or in vitro could provide a booster shot to increase rare stem cell populations that could be used to generate differentiated beta-cells to treat diabetes.